2026-07-26T08:12:59Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/275962026-07-17T00:15:49Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
Alarcón-Ruiz, Iván
author
Ruiz-Rodríguez, María Jesús
author
Martínez-Martínez, Sara
author
Toral, Marta
author
Martín-Bermejo, Noelia
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Mateos-García, Sergio
author
Gil-Ruiz, Teresa
author
Herrero-Galán, Elías
author
Méndez-Olivares, María José
author
López-Maderuelo, Dolores
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Gutiérrez-Martínez, Carolina
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Clemente, Cristina
author
Clemente-Manteca, Alejandro
author
H-Alcántara, Alberto
author
Guala, Andrea
author
Evangelista, Arturo
author
Teixido-Tura, Gisela
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Rodríguez-Puyol, Diego
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Nistal, Juan Francisco
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Alegre-Cebollada, Jorge
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Vázquez, Jesús
author
Duarte, Juan
author
Redondo, Juan Miguel
author
Campanero, Miguel R
2026-07-16T10:20:40Z
2026-07-16T10:20:40Z
2026-07-06
Nat Commun. 2026 Jul 6;17(1):5631.
NATURE COMMUNICATIONS
42409814
https://hdl.handle.net/20.500.12105/27596
Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αβ-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αβ integrin and ILK expression. Disrupting FN assembly or inhibiting αβ, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αβ-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.
eng
Fibronectin-induced overactivation of αβ-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
research article
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Fibronectin-induced overactivation_Nat Commun_2026.pdf